Pharmacological Antagonism of the Slow‐Activating Delayed Rectifying Potassium Channel (IKs) Has No Effect on Cochlear Structure and Function in vivo

The experimental class III antiarrhythmic drug, L-768673, prolongs the refractory period of cardiac myocytes by selectively blocking the slow-activating delayed rectifying potassium (I Ks ) channel. The I Ks channel has also been identified in vestibular dark cells and in the marginal cells of the stria vascularis. In the stria vascularis, the I Ks channel plays an important role in cochlear homeostasis. Genetic null deletion of the I Ks channel in mice and man results in profound hearing loss and cochlear pathology. Therefore, the purpose of the present study was to investigate the effect of L-768673 on the auditory function and cochlear morphology in rats using auditory brainstem-evoked response and light microscopy. Auditory testing was performed one week prior to dosing, following 14 days of administration and 28 days after the completion of dosing. L-768673 (50 or 250 mg/kg/day for 14 days), had no significant effects on auditory function or cochlear morphology. The results of this study suggest that high doses of L-768673 are not toxic to the inner ear of adult rats treated for 14 consecutive days, and that the ototoxic potential of orally administered L-768673 and similar I Ks -selective compounds is unlikely at doses within the therapeutic range.